Innovations in radiation fractionation, planning, and delivery and development of combinations of radiation, with chemotherapy have improved the local-regional control (LRC) of advanced cancers of the upper aerodigestive track (UADT), including head &neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), resulting in better survival but at the expense of increased toxicity. Studies conducted through this project identified the epidermal growth factor receptor (EGFR) as an important determinant of cellular radiation sensitivity, elucidated mechanisms by which EGFR governs cellular response to radiation, and established the combination of radiation with cetuximab (monoclonal antibody against EGFR) as a novel, less toxic, frontline therapy for patients with locally advanced HNSCC. This represents a successful translation from the bench to bedside in merely a nine year time span. However, the results of the pivotal trial showed that there is room for further improvement in LRC and the impact on distant metastasis has been minimal. Emerging data show that high level of insulin-like growth factor receptor 1 (IGF-1 R) expression is associated with resistance to therapy and that crosstalk exists between EGFR and IGF-1 R pathways. We have generated preliminary preclinical evidence showing that cancer cells upregulate IGF-1 R in response to EGFR antagonists. These new findings led us to propose the following hypotheses: (1) constitutive or induced upregulation of IGF-1 R is a major mechanism for lack of enhancement of tumor response to radiation by EGFR antagonist alone and (2) co-targeting both EGFR and IGF-1 R signaling pathways, using their respective monoclonal antibodies cetuximab and A12, in conjunction with radiation will yield superior outcome than blockade of EGFR signaling alone. To test these hypotheses, we propose the following specific aims: 1) determine the direct radiosensitizing effect of A12 on HNSCCs and NSCLCs in vitro;2) optimize the combination of fractionated radiotherapy with A12 using human tumor xenograft models;3) assess the activity of A12 in suppressing invasion and metastatic spread using an bioluminescence imaging method;and 4) assess the effects of combination of radiation with cetuximab and A12. When encouraging, results will serve as the basis for formulating compelling regimen for clinical testing.